Heterocyclic compounds



3,985,094 HETEROCYCLIC C(BMPGUNDS Charles Ferdinand Huehner, Chatharn, N.J., assignor to Ciba Corporation, a corporation of Delaware No Drawing. Filed Feb. 9, 1961, Ser. No. 88,031 6 Claims. (Cl. 260-495) The present invention relates to N-oxides of tertiary amino-lower alkyl-indenes. Primarily, it concerns N- oxides of 3-(pyridyl-lower alkyl)-2(tertiary aminolower alkyD-indenes and the salts thereof.

A pyridyl group in the above compounds represents primarily 2-pyridyl, but may also stand for 3-pyridyl or 4-pyridyl. These pyridyl radicals are preferably unsubstituted or may be substituted by lower alkyl, e.g. methyl, ethyl and the like. Other substituents may be, for example, lower alkoxy, e.g. methoxy, ethoxy and the like, or halogeno, e.g. fiuoro, chloro, bromo and the like, or any other suitable functional groups.

The lower alkyl portion of the pyridyl-lower alkyl radical, which connects the pyridyl group with the indene nucleus, may be represented by a lower alkylene radical having from one to seven, especially from one to three, carbon atoms, e,g. methylene, l,l-ethylene, 1,2ethylene, I-methyI-LQ-et-hylene, 2-methyl-1,2-ethylene, 1,1-propylene, 1,3-propylene or 2,2-propylene, as well as l,1-butylene, 2,2-butylene, 2,3-butylene, 1,4-butylene, 1,5-pentylene and the like.

(The lower alkyl portion of the tertiary amino-lower alkyl group attached to the 2-position of the indene nucleus, may be represented by a lower alkylene radical containing from one to seven, preferably from two to three, carbon atoms; such radicals are, for example, 1,2- ethylene, 1-methyl-1,2-ethylene, 2-methyl-1,2-ethylene or 1,3-propylene, as Well as methylene, 1,1-ethylene, 1- methyl-1,3-propylene, 1,4-buty1ene, 1-methyl-1,4-butylene, 1,5-pentylene and the like. The lower alkylene radical or a portion of it may also be part of a heterocyclic ring system, such as a saturated or partially saturated azacyclic ring system, containing the tertiary amino group as the aza-ring member. Preferably, the lower alkyl portion of the tertiary amino-lower alkyl group contains from two to three carbon atoms and separates the tertiary amino group from the 2-position of the indene nucleus by from two to three carbon atoms.

Disubstituted amino groups, which represent tertiary amino, are, for example, N,N-di-hydrocarbon-amino groups, in which hydrocarbon represents, for example, lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkly, monocyclic carbocyclic aryl, such as phenyl, or monocyclic carbocyclic aryl-lower alkyl, such as phenyllower alkyl. Such radicals contain from one to ten carbon atoms, and may be represented, for example, by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, pentyl, neopentyl, allyl, methylallyl, cyclopentyl, cyclohexyl, cyclopentyl-methyl, phenyl, benzyl, lphenylethyl, 2-phenylethyl and the like. These hydrocarbon radicals may contain further substituents; tree hydroxyl, lower alkoxy, e.g. methoxy, ethoxy and the like, or any other suitable functional group may be attached to such hydrocarbon radicals. N,N-di-lower hydrocarbon-amino groups are primarily represented by N,N-di-lower alkyl-amino, in which lower alkyl contains from one to four carbon atoms, e.g. N,N-dimethylamino, N-methyl-N-ethylamino, N,N-diethylamino, N,N-di-npropylamino, N,N-di-isopropylamino and the like, by N- cycloalkyl-N-lower alkylamino, in which cycloalkyl contains from five to seven ring carbon atoms and lower alkyl contains from one to four carbon atoms, e.g. N-cyclopentyl-N-methyl-amino, N-cyclohexyl-N-methylamino, N-cyclohexyl-N-ethyl-amino and the like, or N- 3,985,094 Patented Apr. 9, 1963 lower alkyl-Nphenyl-lower alkyl-amino, in which lower alkyl contains from one to four carbon atoms, e.g. N- benzyl-N-methyl-amino, N-benzyl-N-ethyl-amino, N- methyl-N( 1-phenylethyl)-amino, N-methyI-N-(Z-phenylethyl)-amino and the like, or any other N,N-di-hydrocarbon-amino group. The hydrocarbon radicals, particularly lower alkyl, may also contain functional groups, such as hydroxyl, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, or any other suitable group as substituents. N,N-di-hydrocarbon-amino groups, in which hydrocarbon contains functional groups as substituents are, for example, N-hydroxy-lower alkyl alkyl- N-lower alkyl-amino, e.g. N-(Z-hydroxy-ethyl)-N-methylamino and the like, N,N-di-hydroxy-lower alkyl-amino, e.g. N,N-di-'(2-hydroxy-ethyl)-amino and the like.

The disubstituted amino group may also be represented by 1-N,N-a-lkylene-imino or by l-N,N-aza-alkyleneimino groups, in which the alkylene portions contain from four to six carbon atoms, as well as by l-N,N-oxaalkylene-imino and by 1-N,N-thia-alkylene-imino, in

,which alkylene contains preferably four carbon atoms.

Together with the nitrogen atom such alkylene, azaalkylene, oxa-alkylene or thia-alkylene radicals represent, for example, 1-N,N-alkylene-imino, in which alkylene contains from four to six carbon atoms, such as l-pyrrolidino radicals, e.g. l-pyrrolidino, Z-methyl-l-pyrrolidino and the like, l-piperidino radicals, e.g. l-piperidino, Z-methyl-l-piperidino, 4-methyl-l-piperidino, B-hydroxyl-piperidino, 3-acetoxy-1-piperidino, 3-hydroxymethyl-1- piperidino and the like, 1-N,N-1,6-hexylene-imino and the like, l-N,N-(aza-alkylene)-irnino, in which alkylene contains from four to six carbon atoms, particularly ,l-N,N- (N-lower alkyl-aza-alkylene)-imino, in which alkylene contains from four to six carbon atoms, such as 1-N,N-(3-aza-l,5-pentylene)-imino, particularly 1- N,N-(3-aza-3-lower alkyl-1,5-pentylene)-imino, e.g. 4- methyl-l-piperazino, 4-ethyl-l-piperazino and the like, as well as 4-hydroxyethyl-l-piperazino, 4-acetoxyethyl-1- piperazino and the like, l-N,N-(3-aZal,6-hexylene)- imino, particularly l-N,N-(3-aza-3-lower alkyl-l,6-hexylene)-imino, e.g. 1-N,N-(3-aza-3-methyl-l,6-hexylene)- imino and the like, or 1-N,N-(4-aza-1,7-heptamethylene)- irnino, particularly 1-N,N-(4-aza-4-lower alkyl-1,7-heptamethylene)-imino, e.g. 1-N,N-(4-aza-4-n1ethyl-1,7-heptamethylene)-imino and the like, 1-N,N-(3-oxa-1,5-pentylene)-imino, e.g. 4-morpholino and the like, 1-N,N-(3- thia-1,5-pentylene)-imino, e.g. l-thiamorpholino and the like.

The tertiary amino-lower alkyl radical may also be represented by a heterocyclic or a heterocyclic-lower alkyl radical, in which the disubstituted amino group is part of the heterocyclic nucleus. Such nucleus may be connected through one of its ring carbon atoms or through a lower alkylene radical, e.g. methylene, 1,2- ethylene and the like, with the 2-position of the indene ring. Such radicals are represented, for example, by 1-methyl-3-pyrrolidinomethyl, 1-methyl-3-piperidinomethyl, 1-methyl-4-piperidino and the like.

The 1-position of the indene nucleus is preferably unsubstituted, or, if substituted, contains primarily a hydrocarbon radical, particularly lower alkyl, e.g. methyl, ethyl and the like, or monocyclic carbocyclic aryl-lower alkyl, e.g. benzyl and the like.

The six-membered carbocyclic aryl portion of the indene nucleus is preferably unsubstituted or may contain one or more than one substituent, which may be located in any of the four positions available for substitution; whenever at least two substituents are present, these may be of the same or of different nature. Such substituents may be, for example, lower alkyl, e.g. methyl, ethyl and the like, halogeno-lower alkyl, e.g. triiluoromethyl, etheri'fied hydroxyl, such as lower alkoxy, e.g. methoxy, ethoxy and the like, or lower alkylenedioxy, e.g. methylenedioxy, esteriiied hydroxyl, such aslower alkoxy-carbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, lower alkanoyloxy, e.g. acetyloxy, propionyloxy and the like, or halogeno, e.g. fiuoro, chloro, bromo and the like, acyl, such as lower alkanoyl, e.g. acetyl, propionyl and the like, etherified mercapto, such as lower alkylmercapto, e.g. methylmercapto, ethylmercapto and the like, nitro, amino, for example, unsubstituted amino, N-mono-substituted amino, such as N-lower alkyl-amino, e.g. N-rnethylamino and the like, or preferably N,N-disubstituted amino, for example, N,N-di-lower alkylamino, e.g. N,N-dimethylamino and the like. The sixmembered carbocyclic aryl portion of the indene ring may, therefore, be represented, for example, by an unsubstituted, a lower alkyl-substituted, a halogeno-lower alkyl-substituted, a lower alkoxy-substituted, a lower alkylenedioxy-substituted, a lower alkoxy-carbonyloxysubstituted, a lower alkanoyloxy-substituted, a halogeno- Substituted, a lower alkanoyl-substituted, a lower alkylmercapto-substituted, a nitro-substituted, an amino-substituted, an N-lower alkyl-amino-substituted or an N,N- di-lower alkyl-amino substituted six-membered carbocyclic aryl portion.

Salts of the N-oxide compounds of this invention are primarily therapeutically acceptable acid addition salts with inorganic or organic acids. Suitable inorganic acids are, for example, mineral acids, such as hydrohalic acids, e.g. hydrochloric, hydrobromic acid and the like, or sulfuric, phosphoric acids and the like. Organic acids are organic carboxylic acids, such as lower aliphatic monocarboxylic acids, for example, lower alkane monocarboxylic acids, e.g. formic, acetic, propionic, pivalic acid and the like, lower alkene monocarboxylic acid, e.g. 3-butene carboxylic acid and the like, hydroxy-lower alkane monocarboxylic acids, e.g. glycolic, lactic acid and the like, lower alkoXy-lower alkane monocarboxylic acids, e.g. methoXy-acetic, ethoXy-acetic acids and the like, lower alkanoyl-lower alkane monocarboxylic acids, e.g. pyruvic acid and the like, halogeno-lower alkane monocarbcxylic acids, e.g. chloroacetic, dichloroacetic, trichloroacetic, bromoacetic acid and the like, lower aliphatic dicarboxylic acids, for example, lower alkane dicarboxylic acids, e.g. oxalic, malonic, succinic, methyl-succinic, dimethylsuccinic, glutaric, a-methylglutaric, a,a-dimethylglutaric, B-methylglutaric acid and the like, lower alkane dicarboxylic acid halfesters with lower alkanols, e.g. succinic acid monomethyl ester, glutaric acid monoethyl ester and the like, lower alkene dicarboxylic acids, e.g. itaconic, homoitaconic, maleic, citracom'c, homocitraconic, pyrocinchonic, xeronic, fumaric acid and the like, lower alkene dicarboxylic acid halfesters with lower alkanols, e.g. maleic acid monoethyl ester and the like, hydroxylower alkane dicarboxylic acids, e.g. malic, tartaric acid and the like, as well as their optically active forms, lower alkoxy-lower alkane dicarboxylic acids, e.g. a,[3-dimethoxysuccinic and the like, lower alkoxy-lower alkene dicarboxylic acid, e.g. ethoxy-maleic acid and the like, halogeno-lower alkane dicarboxylic acids, e.g. chlorosuccinic, bromosuccinic acid and the like, lower aliphatic tricarboxylic acids, for example, lower alkane tricarboxylic acids, e.g. tricarballylic acid and the like, lower alkene tricarboxylic acids, e.g. aconitic acid and the like, hydroxy-lower alkane tricarboxylic acids, e.g. citric acid and the like, cycloaliphatic monocarboxylic acids, such as cycloalkane monocarboxylic acids, e.g. cyclohexane carboxylic acid and the like, cyclo-aliphatic dicarboxylic acids, such as cycloalkene dicarboxylic acids, e.g. tetrahydrophthalic acid and the like, cycloaliphatic-hydrocarhon-lower aliphatic monocarboxylic acids, such as cycloalkyl-lower alkane monocarboxylic acids, e.g. cyclopentylpropionic acid and the like, monocyclic or bicyclic carbocyclic aryl carboxylic or car-bocyclic aryl-lower aliphatic carboxylic acids, e.g. benzoic, dihydrocinnamic, cinnamic, mandelic, salicylic, 4-aminosalicylic, Z-phenoxy-benzoic, Z-acetoxybenzoic acid and the like, or monocyclic or bicyclic carbocyclic aryl-dicarboxylic acids, e.g. phthalic acid, and the like, monocyclic or bicyclic heterocyclic aryl carbocyclic acids, e.g. nicotinic, isonicotinic, 6-quinoline carboxylic, thienoic, furoic acid and the like, or any other suitable carboxylic acid. In addition, amino carboxylic acids, e.g. methionine, tryptophane, lysine, arginine, aspartic, glutamic, hydroxyglutamic acid and the like, organic sulfonic acids, such as lower alkane sulfonic acids, e.g. methane sulfonic, ethane sulfonic acid and the like, lower hydroxy-alkane sulfonic acids, e.g. 2-hydroxyethane sulfonic acid and the like, carbocyclic aryl sulfonic acids, such as monocyclic carbocyclic aryl sulfonic acids, e.g. p-toluene sul-fonic acid and the like or mixtures of acids, such as the mixture known as tannic acid, are suitable for salt formation. Particularly useful are acid addition salts with mineral acids, lower alkene dicarboxylic acids, e.g. maleic, citraconic acid and the like, lower hydroxy-alkane dicarboxylic acids, e.g. malic, tartaric acid and the like, hydroxy-lower alkene dicarboxylic acids, e.g. hydroxymaleic, dihydroxymaleic acid and the like, or hydroxy-lower alkane tricarboxylic acid, e.g. citric acid and the like.

Salts, which may be prepared primarily for identification purposes, are, for example, those with acidic organic nitro compounds, e.g. picric, picrolonic, flavianic acid and the like, or metal complex acids, e.g. phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like.

Monoor poly-salts may be formed depending on the number of salt-forming groups and/or the conditions used for the salt formation.

Depending on the number of asymmetric carbon atoms, the indene compounds of this invention may be obtained as mixtures of racemates, racemates or antipodes, the separation and resolution of which will be discussed and illustrated hereinbelow.

The new compounds of this invention show antihistaminic effects and are intended to be used as antihistaminic agents to relieve allergic disorders, especially those caused by an excess of histamine; such allergic conditions are, for example, hay fever, urticaria, allergies caused by food, plant pollen or medicinal agents, and the like. In addition, compounds of this invention have a central nervous system depressing effect, thus exert sedative and quieting properties; they can, therefore, be used as sedative agents to counteract states of nervousness, anxiety, stress or shock, as well as local anesthetic eifects, which render these compounds useful as local anesthetics, for example, in connection with minor surgery and the like.

Compounds with particularly outstanding antihistaminic properties are N-oxides, particularly mono-N- oxides, of compounds of the formula:

in which R attached to any of the positions available for substitution, represents hydrogen, lower alkyl containing from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, lower alkoxy containing from one to four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, or halogeuo having an atomic weight below 80, e.g. fluoro, chloro or bromo, R represents hydrogen or lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, A stands for alkylene containing from one to three carbon atoms, e.g. methylene, 1,1-ethylene, 1,2- ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene or 2,2 propylene, Py represents pyridyl or lower alkyl-substituted pyridyl, A stands for lower alkylene containing from one to three canbon atoms, particularly for lower alkylene, which contains from two to three carbon atoms and separates the group Am from the 2-position of the indene nucleus by from two to three carbon atoms, i.e. 1,2-ethylene, 1-methyl-l,2-ethylene, 2-methyl-l,2-ethylene or 1,3-propylene, and Am represents N,N-di-lower alkylarnino, in which lower alkyl contains from one to four carbon atoms, e.g. N,N-dimethylamino, N-ethyl-N- methyl-amino, N,N-diethylamino, N,N-di-n-propylamino, N,N-di-isopropylamino, N,N-di-n-butylamino and the like, N-cycloalkyl-N-lower alkyl-amino, in which cycloalkyl contains from five to seven ring carbon atoms and lower alkyl contains from one to four carbon atoms, e.g. N-cyclopentyl-N-methyl-amino, N cyclopenty-l-N-n-propylamino, N cyclohexyl-N-ethyl-amino, N cycloheptyl-N- methyl-amino and the like, N-lower alkyl-N phenyl-lower alkyl amino, in which lower alkyl contains from one to four carbon atoms, e.g. N-benzyl-N-methyl-amino, N-benzyl-N-ethyl-amino, N-methyl-N-(l-phenylethyl)-amino, N- methyl-N- 2-phenylethyl) -amino, N-methyl-N- 3-phenylpropyl)-amino and the like, 1-N,N-lower alkylene-imino, in which lower alkylene contains from four .to seven carbon atoms, e.g. l-pyrrolidino, l-piperidino, 1-N,N-(1,6- hexylene)-imino and the like, 4-morpholino, 1-N,N-(N- lower alkyl-aza-alkylene)-imino, in which alkylene contains from four to six carbon atoms, particularly 4-lower alkyl-l-piperazino, e.g. 4-methyl-1-piperazino, 4-ethyl-1- piperazino, and the like, as well as l-N,N-(3-aza-3-methyll,6-hexylene)imino, l-N,N-(4-aza-4-methyl-l,7 heptylene)-imino and the like, and in which the N-oxide oxygen is preferably attached to the nitrogen atom of the tertiary amino group Am, and the therapeutically acceptable acid addition salts thereof.

This group of compounds may be represented by the mono-N-oxides of 2-(N,N-di-lower alkyl-amino-lower alkyl)-3-[-(2-pyridyl)-lower alkyl]-indenes, in which lower alkyl of the N,N-di-lower alkyl-amino group contains from one to four carbon atoms, lower alkyl, separating the N,N-di-lower alkyl-amino group from the 2-position of the indene nucleus by from two to three carbon atoms, contains from two to three carbon atoms, and lower alkyl of the (2-pyridyl)-lower alkyl portion contains from one to three, preferably from one to two, carbon atoms, and in which the N-oxide oxygen is attached to the nitrogen atom of the N,N-di-lower alkyl-amino group, and the therapeutically acceptable acid addition salts thereof.

Outstanding properties are exhibited by 2(2-N,N-dimethylaminoethyl) 3 [1 (2-pyridyl)-ethyl] -indene N- oxide of the formula:

HaC-EHQ either in the form of its racemate or the optically active forms, particularly the levo-rotatory l-form, and salts of these compounds with therapeutically acceptable acids, such as mineral acids, e.g. hydrochloric, hydrogromic, sulfuric, phosphoric acids and the like, lower alkene dicarboxylic acids, eg. itaconic, maleic acid and the like,

lower alkyl of (4-pyridyl)-lower alkyl and (3-pyridyl)- lower alkyl, respectively, contains from one to three carbon atoms, and in which lower alkyl, separating the N,N- di-lower alkyl-amino group from the 2-position of the indene nucleus by from two to three carbon atoms, stands for an alkylene radical having from two to three carbon atoms, and the N-oxide oxygen atom is attached to the nitrogen atom of the N,N-di-lower alkyl-amino group, and their therapeutically acceptable acid addition salts; these compounds show remarkable antihistaminic eifects.

The new compounds of this invention may be used as medicaments in the form of pharmaceutical preparations,

which contain the new indene N-ox-ide derivatives, in-, cluding racemates, .antipodes, and the therapeutically acceptable acid addition salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid vehicle suitable for enteral or parenteral administration. To relieve allergic skin troubles, the new indene compounds may also be employed topically. For making up the preparations there may be used substances, which do not react with the new compounds, such as water, gelatine, lactose, starches, lactic acid, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, propylene glycol, polyalkylene glycols or any other carrier used in the art of manufacturing medicaments. The pharmaceutical preparations may be in solid form, for example, as capsules, tablets, dragees, and the like, in liquid form, for example, as solutions, suspensions, emulsions and the like, or in the form of salves, creams, lotions and the like for topical administration. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers, etc. They may also contain, in combination, other therapeutically useful substances.

The compounds of the present invention may be prepared by treating a S-(pyridyl-lower aJkyD-Z-tentiary amino-lower alkyl-indene or a salt thereof with an N- oxidation reagent, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a resulting free compound into a salt thereof.

The treatment with an N-oxidation reagent is carried out according to known methods. For example, a solution of the starting material in an inert solvent is treated with the N-oxidation reagent. Suitable reagents are, for example, ozone, hydrogen peroxide, inorganic pera'cids, e.g. persulfuric acid and the like, organic per-sulfonic acids, e.g. p-toluene persu-lfonic acid and the like, or primarily organic percarboxylic acids, e.g. peracetic acid, perbenzoic acid, monoperphthalic acid and the like. Inert solvents are, for example, halogenated lower aliphatic hydrocarbons, e. g. methylene chloride, chloroform, ethylene chloride and the like, monocyclic carbocyclic aryl hydrocarbons, e.g. benzene, toluene and the like, or any other suitable, inert solvent employed in N-oxidation reactions.

The reaction is preferably carried out at room temperature, or, if necessary, while cooling; it may also be performed in the atmosphere of an inert gas, erg. nitrogen and the like.

The starting materials used in the above N-oxidation reaction may be prepared according to the procedure described in my patent application Serial No. 18,815, filed March 31, 1960, of which the present application is a continuation-in-part application.

Compounds of the present invention, as well as the starting materials, which contain more than one asymmetric tatom, may be obtained in the form of mixtures of tracemates. Such mixtures of racemates may be separated into individual racernic compounds or salts thereof, using known methods, which may be, for example, based on physico-chemical differences, such as solubility. Thus, mixtures of racenia-tes may be separated by fractionate crystallization, if necessary, by using a 7 derivative, e.g. a salt, of a mixture of racemates, by fractionated distillation and the like.

Separated raccm ates or racemates of compounds which contain one asymmetric carbon atom only, may be resolved into the optically active forms, the levo-rotatory l-form and the dextro-rotatory d-form. Such resolution procedure may be carried out according to methods which are suitable for the separation of a racernate. For example, to a solution of the free base of a racemate (a d,lcompound) in an inert solvent or a mixture of solvents, is added one of the. optically active forms of an acid, containing an asymmetric carbon atom, or a solution thereof. Especially useful as optically active forms of saltaforming acids, having an asymmetric carbon atom, are the d-tartaric acid (L-tartaric acid) and the l-tartaric acid (D-tartaric acid); the optically active forms of di-- benzoyl tartaric, di-p-toluyl-tartaric, malic, mandelic, 10- camphor sulfonic acid, quinic acid and the like, may also be used. The salts, which are formed by the optically active forms of the base with the optically active form of the acid may then be isolated, primarily on the basis of their different solubilities. The free and optically active base may be obtained from a resulting salt according to methods known for the conversion of a salt into a base, for example, as is outlined here-inbelow. An optically active base may be converted into a therapeutically useful acid addition salt with one of the acids mentioned hereinbefore, for example, according to the methods described hereinbelow. The optically active forms may also be isolated by biochemical methods.

The indene N-oxide compounds of this invention may be obtained in the form of the free bases or as the salts thereof. A salt may be converted into the free base, for example, by reaction with an alkaline reagent, such as aqueous alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, aqueous alkali metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate and the like, ammonia,

such as aqueous ammonia, ammonia in a lower alkanol,

e.=g. methanol, ethanol, and the like, or any other suitable basic reagent, such as, for example, an anion exchange resin. A free base may be converted into its therapeutically useful acid addition salts by reacting the former with one of the acids mentioned hereinbefore according to known methods. The salts may also be obtained as the hemihydrates, monohydrates, sesquihydr-ates or poly hydrates depending on the conditions used in the formation of the salts. Monoor poly-salts may be formed according to the conditions used in the procedure for the preparation of the salts and/ or the number of salt-form ing groups present.

This is a continuation-in-part application of my application Serial No. 18,815, filed March 31, 1960, which in turn is a continuation-in-part application of my application Serial No. 852,208, filed November 12, 1959', now abandoned, which in turn is a continuation-in-part application of my application Serial No. 825,886, filed July 9, 1959, now US. Patent No. 3,036,085, which in turn is a continuation-impart application of my application Serial No. 810,998, filed May 5, 1959, now US. Patent No. 2,947,756, which in turn is a continuation-in-part application of my application Serial No. 792,263, filed February 10, 1959, which in turn is a continuation-in-part application of my application Serial No. 771,225, filed November 3, 1958, now US. Patent No. 2,970,149, which in turn is a continuation-in-part application of my application Serial No. 754,526, filed August 12, 1958.

The following example is intended to illustrate the invention and is not to be construed as being a limitation thereon. Temperatures are given in degrees Centigrade.

Example 1.75 g. of 2 (2 N,N dimethylaminoethyl)-3-[1-(2- pyridyl)-ethyl]-indene maleate is suspended in 5 ml. of water, made strongly basic with ammonia and extracted with ether. The ether is evaporated to dryness leaving afiree base, which is dissolved in 2 ml. of ethanol and treated with 0.5 ml. of 30% hydrogen peroxide. After standing 24 hours at room temperature, the excess hydrogen peroxide is destroyed by adding a catalytic amount of platinum oxide. The latter is removed by filtration and the filtrate evaporated to dryness. 0.5 g. of maleic acid in 3 ml. of ethanol is added to the residue, containing the 2- 2-N,N-dimethylaminoethyl) -3-[ 1- (2-pyridyl) -ethyl]-indene N-oxide of the formula:

o-bmomr rwnm g 0 and the solution evaporated to dryness leaving the 2-(2- N,N-dimethylaminoethyl)-3-[1-(2-pyridyl)-ethyl] indene N-oxide maleate as a noncrystalline powder. The corresponding picrate melts at 160.

Other N-oxides, such as the l-2-(2-N,N-dimethylaminoethyl) -3- l-(2spyridyl -ethyl] -indene N-oxide, 2- (2-N,-N- dimethylaminoethyl) -3- Z-pyridyl) -et-hyl] -indene N-oxide, 2-(2-N,N-dirnethylamino-2-rnethyl-ethyl)-3-[l-(2 pyridyl) -ethyl] -indene, 2- (2-N,N-dimethylaminoethyl) -3- (4- pyridyl) -methyl] -indene, 2- (2-N,N-dimethylaminoethyl) 3-[(3-pyridyl)-methyl]-indene and the like, may be prepared according to the above procedure using the appropriate starting materials.

The starting material used in the above procedure may be prepared as follows: 33.2 g. of dhydropyran is slowly added to a stirred mixture of 50 g. of or-benzyl-malonic acid and 0.1 g. of p-toluene sulfonic acid in ml. of diethylether kept at 30 during the addition of the dihydropyran. The mixture is stirred for an additional 15 minutes and then poured onto ice. The ether phase is washed with aqueous potassium carbonate, then with water and is dried over magnesium sulfate; the ether is evaporated under reduced pressure by keeping the temperature below 30 to yield the ditetrahydropyranyl m benzyl-malonate. A toluene solution of this ester is gradually given to a solution of 4.86 g. of a 50% suspension ofnsodiurn hydride in mineral oil while heating and stirring for six hours. A solution of 10.8 g. of 2-N,N-dimethylaminoethyl chloride in toluene is added dropwise, and the re action mixture is refluxed for an additional 48 hours. The toluene layer is washed with water, dried over magnesium sulfate and evaporated to yield the di-tetrahydropyranyl a-benzyl-ow(2-N,N-dimethylaminoethyl)-malo nate; yield: 32.2 g. of crude material.

A mixture of the resulting di-tetr-ahydropyranyl ocbenzyl-a-(2-N,N-dimethylaminoethyl)-malonate in 180 g. of polyphosphoric acid is stirred at 110-120 during thirty minutes, and then at during an additional twenty minutes. The reaction mixture is cooled, poured into ice-water, the acidic phase is neutralized with potassium carbonate and extracted with ether. The ether solution is washed with 15 percent aqueous hydrochloric acid solution, the aqueous layer is neutralized with potassium carbonate and again extracted with ether. After washing the ether layer with water and drying it over magnesium sulfate, the solvent is evaporated to yield the 2-(2-N,N-dimethylaminoethyl)-indan-1-one, yield: 8 g. of crude material. The hydrochloride of the base melts at after recrystallization from a mixture of ethanol and et er.

26 g. of Z-ethyl-pynidine is added dropwise to a stirred solution of 650 ml. of an 0.37 molar solution of phenyl lithium benzene. The addition is carried out in an atmosphere of nitrogen and while cooling to 20. After two hours a solution of 10 g. of 2-(2-N,N-dimethylaminoethyl)-indan-1-one in 50 ml. of dry ether is added over a period of five minutes while stirring and cooling to room temperature. After standing for twenty-four hours the organo-lithium compounds are decomposed by the addition of 50 ml. of water with external cooling. After separating the water phase from the organic solution, the latter is washed several times with 50 ml. of water, and then extracted with a mixture of 40 ml. of concentrated hydrochloric acid and 100 ml. of water.

The acidic solution, containing 2-(2-N,N-dimethylaminoethyl)-1-[1-(2-pyridy1)-ethyl]-indan-l-ol, is heated on the steam hath for thirty minutes to effect complete dehydration to the desired indene derivative. The solution is cooled, made strongly basic with an aqueous solution of ammonia and then extracted with ether. The ether phase is dried over sodium sulfate, filtered, evaporated, and the residue is distilled. At 15 mm. pressure, the excess of Z-ethyl-pyridine is removed, at l20/0.5 mm. some unreacted 2-(2-N,N-dimethylaminoethyl)-indan-oone distills and at 165-l75/05 mm. the 2-(2-N,N-dimethylaminoethyl) -3-[ 1-(2-pyridyl) ethyl] -indene is col- Clected.

To a solution of 1.0 g. of 2-(2N,N-dimethylaminoethyl) -3-[l-(2pyridyl) -ethyl]-indene in ml. of ethanol is added while stirring and heating 0.4 g. of maleic acid. *On cooling the 2-(2-N,Ndimethylaminoethyl)-3-[1-(2- pyridyl)-ethyl] -indene maleate crystallizes, is filtered off, washed with a small amount of ethanol and recrystallized from ethanol, M.P. 158.

What is claimed is:

1. A member of the group consisting of N-oxides of a compound of the formula:

A1-PY R1 2 C-A:Am

in which "R represents a member of the group consisting of hydrogen, lower alkyl, lower alkoxy and halogeno, R stands for a member of the group consisting of hydrogen and lower alkyl, A stands for alkylene having from one to three carbon atoms, Py represents a member of the group consisting of pyridyl and lower alkyl-substituted pyridyl, A stands for lower alkylene, and Am stands for a member of the group consisting of N,N-di-lower alkylamino, N-cycloalkyl-N-lower alkyl-amino, in which cycloalkyi has from five to seven ring carbon atoms, N-lower 10 alkyl-N-phenyl-lower alkyl-amino, l-N,N-lower alkyleneimino, in which lower alkylene has from four to seven carbon atoms, 4-morpholino, 4-lower alkyl-l-piperazino, l-N,N-(3-aza-3-methyl-1,6-hexylene)-imino and 1-N,N- (4-aza-4-methyl-1,7-heptylene)-imino, and therapeutically acceptable acid addition salts of such N-oxides.

2. The mono-N-oxide of 2-(N;N-di-lower alkyl-aminoiower alkyl) -3-[(2-pyridyl)-lower alkylJ-indene, in which lower alkyl, separating the N,N-di-lower alkyl-amino group from the 2-position of the indene nucleus by trom two to three carbon atoms, has from two to three carbon atoms, and lower alkyl of the (2-pyridyl)-lower alkyl portion has from one to three carbon atoms, and in which the N-oxide oxygen is attached to the nitrogen atom of the N,N- di-lower alkyl-amino group.

3. Therapeutically acceptable acid addition salts of the mono-N-oxide of 2-(N,N-di-lower alkyl-amino-lower alkyl)-3-[(2-pyridyl)-lower alkyl]-indene, in which lower alkyl, separating the N,N-di-lower alkyl-amino group from the 2-position ot the indene nucleus by from two to three carbon atoms, has from two to three carbon atoms, and lower alkyl of the (2-pyridyl)-iower alkyl portion has from one to three carbon atoms, and in which the N-oxide oxygen is attached to the nitrogen atom of the N,N-di' References Cited in the file of this patent UNITED STATES PATENTS Huebner Aug. 2, 1960 OTHER REFERENCES Sidgwick: The Organic Chemistry of Nitrogen, 2nd edition, pages 166-7, Oxford (1937).

Noller: Chemistry of Organic Compounds, 2nd edition, page 240 (Saunders) (1957). 

1. A MEMBER OF THE GROUP CONSISTING OF N-OXIDES OF A COMPOUND OF THE FORMULA:
 6. THE MALEATE OF THE MONO-N--OXIDE OF 2-(2-N,N-DIMETHYLAMINOETHYL)-3- 1-(2 - PYRIDYL)-ETHYL! - INDENE, IN WHICH THE N-OXIDE OXYGEN ATOM IS ATTACHED TO THE NITROGEN ATOM OF THE N,N-DIMETHYLAMINO GROUP. 